CYSTIC-FIBROSIS - A DISEASE OF ALTERED PROTEIN-FOLDING

Cystic fibrosis (CF) is caused by mutations in the gene that encodes t he cystic fibrosis transmembrane conductance regulator, CFTR. Previous ly we demonstrated that the common Delta F508 mutation in the first nu cleotide binding domain (NBD1) alters the ability of the domain to fol d into a functional three-dimensional structure, providing a molecular explanation for the observation that the mutant CFTR is retained in t he endoplasmic reticulum and does not traffic to the apical membrane o f affected epithelial cells. Notably, when conditions are altered to p romote folding of the mutant protein, it can assume a functional confo rmation. Correcting the folding defect may have therapeutic benefit fo r the treatment of cystic fibrosis. Here we summarize these results an d discuss the implications in vitro folding studies have for understan ding the pathobiology of CF.